1. Field of the Invention
This invention, in part, relates to anti-craving as mediated by substances which reduce the desire for euphoriants, specifically alcohol and opiates. In this invention craving means obsessive compulsion, excessive desire for and indulgence in substances which are classed as psychoactive drugs and/or act which enhance the effect of endogenous and/or exogenous neuropeptides, neurotransmitters and psychoactive agents, respectively. Psychoactive drugs include but are not limited to alcohol, opiates, and food. Anti-craving medicaments result in a reduction in the excessive behavior desired. Substances which prevent the destruction or enhance the content or action of brain chemicals, enkephalins, endorphins, opioid transmitters, opioid receptors are described as anti-craving agents. Furthermore, in this application the term neuropeptidyl opiates (NPO) includes both brain endorphins and enkephalins; and an euphoriant includes but is not limited to alcohol, opiates, nicotine, food and sexual acts.
More particularly, this invention relates to a treatment of animals and humans by administering substances which inhibit and/or delay the inherent breakdown of a class of naturally occurring peptidyl opiates or euphoriants that are created and exist within mammals as well as altering the function and content of other neurotransmitter substances which interact with the endorphinergic transmitter systems in the nervous system and with opioid receptor function. Such neurotransmitter substances include but are not limited to glutamine, gamma-amino-butryic-acid (GABA), serotonin, and norepinephrine.
2. Description of the Prior Art
Enkephalins and endorphins are opiate-like substances which have recently been discovered to be endogenous in various animal species, including mammals and man, whereby the general term endorphins includes but is not limited to B-endorphin, methionine-enkephalin, and leucine-enkephalin. Enkephalins and endorphins are peptides and/or polypeptides normally present in the brain.
As pointed out in U.S. Pat. No. 4,439,452, it has heretofore been observed that enkephalins and endorphins have an ability to act as analgesics when administered to various animals and humans by certain special routes, including intracerebral injections. The major drawbacks of utilizing these endogenous substances directly for therapeutic purposes are their extremely labile nature and poor penetration into the brain via oral administration. It is known that the destruction of the endogenous enkephalins and/or endorphins is due to the action of certain enzymes which resemble carboxypeptidase or endopeptidase (catalepsin), respectively. These and other enzymes which inactivate enkephalins and endorphins are known collectively as enkephalinases and endorphinases. An enkephalinase inhibitor is a substance which inhibits a class of enzymes known as enkephalinases, an endorphinase inhibitor is a substance which inhibits a class of enzymes known as endorphinase, said enzymes destroy the neuropeptides, enkephalin and endorphin in the animal body, Blum, K., Handbook of Abusable Drugs, Gardner Press, New York, 1984.
Substances known to alter or decrease alcohol preference in rodents include but are not limited to alanine, fructose, amphetamine, alloxan, endorphin, methionine enkephaline, opiates, narcotic antagonists, and estrogens.
The age old question of whether alcoholism is a psychiatric illness or a biological disease with a specific cause and thus a probable "cure" is still being asked by professionals in the field and is quite controversial.
Scrutiny of the literature reveals that during the past decade certain theories on the etiology of alcoholism includes the interaction of alcohol and opiates in terms of their behavioral and pharmacological actions and resultant addiction to these psychoactive substances may be due to similar biochemical mechanisms.
Following the first suggestion of dual addiction, research in mice refuted this possibility on the basis that dependence to ethanol in mice was not altered by the narcotic antagonist, Naloxone, and according to some workers there is a lack of evidence for the relationship between ethanol and opiates. In this regard, it was stated that since the personality as well as medical symptoms of opiate addicts compared to alcoholics is so distinctly different that to consider commonality is not only improbable, it is unreasonable.
Reports from a few investigators indicated that alcohol ingestion leads to the formation of by-products termed tetrahydroisoquinolines (TIQ's) which are alkaloid condensation products of ethanol metabolism and can be found in the poppy plant where opium is extracted. In simpler terms, it was proposed that when one consumes ethanol in essence that person is ingesting an opiate. In this regard the inventors propose the "link" hypothesis whereby TIQ's can act as an opiate and thus bridge the gap between these two distinct addictive agents. This met with a series of reports which was based on empirical data refuting the "link" hypothesis. The prime controversy was that it was difficult to detect significant amounts of the TIQ's in the brains of animals exposed to ethanol.
Additional work suggests that the TIQ's directly interacts at opiate receptor sites in the brain of rodents. However it was pointed out that this interaction was at a 10-4 molar concentration in vitro assays and thus was much too weak and therefore was not considered as a strong alcohol-opiate link. Furthermore, the brain amounts of the TIQ's and metabolites in mice consuming alcohol was not considered physiologically significant. While some studies show that both the actions of ethanol and TIQ's are blocked by the narcotic antagonist, Naloxone, other research did not support these findings in both animals and humans. A most controversial finding involved the abnormal induction of alcohol drinking by infusions of a variety of TIQ's. This finding is still controversial and remains a question for study. The conclusion reached from publications which support but in no way prove the correlation between TIQ's and ethanol and opiates are: opiates and ethanol act through the opiate receptors; and TIQ's directly or indirectly interact at induced abnormal ethanol drinking in rodents.
An observation which raises an important question with regard to common receptor interaction of opiates and ethanol is that opiate addicts using methadone replacement therapy continue to have euphoriant effects from the ingestion of alcohol. In this regard there are reports showing enhanced alcohol drinking in patients receiving methadone. Without definitive experiments it is conjectured that ethanol through TIQ's act on the endogenous delta receptor site rather than the mu site and thus during mu receptor blockade with narcotics like methadone, which does not bind well to the delta site, alcohol-induced euphoria is obtained. We are further taught that pain killers like morphine do not decrease alcohol consumption and this distinguishes simple analgesia from alcohol abuse and alcoholism.
This then further raises the questions that although endorphins or enkephalins possess analgesic qualities and since ethanol is a simple two carbon molecule and not a benzyl alkaloid and is without significant analgesic properties, it is very difficult to envision a common mechanism of action of these diverse classes of drugs particularly being mediated by the endogenous endorphinergic system.
In spite of this unobvious rationale, the inventors decided to systematically determine the involvement of endorphins and enkephalins in ethanol actions. An important issue that still remains is the concept of alcoholism being genetically influenced.
Early investigations by the inventors further support the correlation between alcohol, opiates, and neuropeptidyl opiates.
In this regard the finding of alcohol preferring mice having somewhat lowered brain enkephalins compared to non-alcohol preferring mice does not answer the problem of cause and effect in terms of alcohol desire. From animal and human experiments it is not clear that brain levels of endorphins and/or enkephalins act as a determinant for craving behavior in general. In fact, there has been one study which found an environmentally-induced reduction of brain enkiphalins in rodents exposed to ethanol during gestation without having significant effects on ethanol preference of the offspring.
Neverless, the inventors describe in this application the discovery of enkephalinase and/or endorphinase inhibitors, substances which raise the levels of endogenous neuropeptidyl opiates naturally without causing addiction by themselves, as novel anti-craving agents including but not limited to alcohol abuse. It also describes the method of treatment and dosage range of certain of these enkephalinase inhibitors to interfere with the compulsive impulse to over-indulge in alcoholic beverages. It further describes the composition of a fortified combination which effects not only the endorphinergic system but also other neurotransmitter systems involved in craving behavior.
Reduced craving in human alcoholics is not achieved with typical ant-depressant medication such as tricyclic anti-depressants, or analgesic agents such as methadone wherein alcohol consumption goes up, or by disulfram therapy. Alcoholism is now classified by the National Council on Alcoholism as a biogenetic disease which is one component of a more general condition commonly known as Obsessive Compulsion Behavioral Disorder. Other types of compulsion include drug seeking, smoking, eating disorders (buleria), sexual promiscuity, and gambling. The National Council on Alcoholism recognizes alcoholism as a disease and not simply a psychosocial phenomenon and has developed definite criteria for the diagnosis and treatment of this illness.
Adult Children of Alcoholics Foundation reports twenty-eight million Americans have been recognized as potential high risk individuals. These persons have an associated syndrome which includes lowered self esteem, lack of well being, fear, anger, depression, and compulsive behavior. Alcoholism is considered to be a biogenetic disease which may be due, in part, to a brain imbalance of neuropeptidyl opiates.